Adriamycine is an antibiotic compound which is useful in the treatment of certain tumors and is described and claimed in U.S. Pat. No. 3,590,028 to Arcamone, et al. A further procedure for the preparation of adriamycin will be found in U.S. Pat. No. 3,803,124 to Arcamone, et al. Said patent also discloses that adriamycin may be prepared from daunomycin or its aglycone daunomycinone. Another approach may be found in Kende, et al, U.S. Pat. No. 4,070,382.
Most synthetic routes to adriamycin are directed to the synthesis of the tetrahydroxytriketo anthracycline known as daunomycinone. In the synthesis of daunomycinone and its known analogs certain synthetic problems have been noted by workers skilled in the art. Daunomycinone itself carries a methoxy group at the 4-position in the D ring of the anthracycline nucleus. The 4-hydroxy analog, carminomycin is also known, as well as other analogs bearing different substituents at the 1,-2,-3,- and 4-positions of the D ring (see Kende, et al, U.S. Pat. No. 4,021,457.
While several approaches to the synthesis of daunomycinone and its analogs have been disclosed in the art, one of principal difficulties encountered in these syntheses is the provision of regiospecificity in the D ring utilizing regularly available starting materials in a process which is economically feasible on the industrial scale. It will be recognized that where regiospecificity of the substituent (if present) in the D ring is lacking the process utilized would automatically carry a 50% yield penalty to the desired end product regardless of the efficiency of the remaining steps.
The remaining recognized problems of the synthesis of daunomycinone and its analogs lie in possession of the desired substitution pattern at the 7- and 9-positions of the A ring of the anthracycline skeleton. The problems are namely; the provision of an alpha hydroxy group at the 7-position, the provision of an alpha hydroxy group at the 9-position and the provision of a 9-beta acetyl group.
It is of interest in planning molecular modifications of daunomycinone to be able to provide, at the 9-beta position, a substituted carbonyl group other than acetyl for example, propionyl, butyryl, benzoyl, and the like.
The conversion of 7,9-dideoxydaunomycinone to daunomycin is a known procedure set forth in Sih et al., Tet. Lett. 3385 (1976) and Kende, et al, J. American. Chemical Society 97, 4425 (1974), the disclosure of which is incorporated herein by reference.